title: Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.
abstract: BACKGROUND
  Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.
  
  
  OBJECTIVE
  To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.
  
  
  RESULTS
  MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E-deficient mice and suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-κB-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-α3, an effect that reduced NF-κB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-κB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-κB nuclear translocation in leukocytes does not involve importin-α3, but rather importin-α5, which miR-181b does not target, highlighting that inhibition of NF-κB signaling in the endothelium is sufficient to mediate miR-181b's protective effects.
  
  
  CONCLUSIONS
  Systemic delivery of miR-181b inhibits the activation of NF-κB and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as atherosclerosis.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Shaolin
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: A K M
authors.initials: AKM
authors.lastname: Wara
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Eugenia
authors.initials: E
authors.lastname: Shvartz
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Yevgenia
authors.initials: Y
authors.lastname: Tesmenitsky
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Nathan
authors.initials: N
authors.lastname: Belkin
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Dazhu
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D028884:Karyopherins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C529100:mirn181 microRNA, mouse
keywords: NF-κB; atherosclerosis; endothelial cells; inflammation; karyopherins; microRNAs